The Eye in Pulmonary Disorders
Joseph Panarelli
Richard B. Rosen
Joseph B. Walsh
In the early phases of pulmonary disease, before the development of significant changes in blood gas constituents, there are no ocular findings. When hypercapnia appears, however, a retinal picture emerges that is the same regardless of the underlying disorder. Chronic or intermittent retention of carbon dioxide occurs in various forms of obstructive disease including asthma, pulmonary emphysema, Pickwickian syndrome (sleep apnea), cystic fibrosis of the pancreas, bronchiectasis, kyphoscoliotic lung disease, surgical or traumatic loss of pulmonary substance, and tuberculosis or other pulmonary infections. Hypoxemia without hypercapnia, noted in restrictive lung diseases and disorders of oxygen transport, produces ocular changes that are more diverse. Restrictive disorders involve reduced oxygen diffusing capacity and include entities such as pneumoconioses, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis, pulmonary alveolar proteinosis, diffuse neoplasms, and connective tissue disorders. Oxygen transport disorders include carbon monoxide poisoning, anemia, and circulatory deficiencies. The initial ocular manifestation of chronic pulmonary disease varies, but when hypoxia occurs, the arterial oxygen desaturation (oxygen tension <75 mm Hg) may be reflected in the ocular vasculature as a darkening of the blood column in the conjunctiva and retinal vessels. The ocular tissues may take on the dusky color of cyanosis when the absolute concentration of desaturated hemoglobin exceeds 5 mg per mL.1 Retinal vascular flow increases markedly in response to diminished oxygen availability, but the changes in vessel caliber cannot be easily appreciated ophthalmoscopically. As chronic lung disease progresses from shortness of breath on exertion to shortness of breath at rest, the increasing carbon dioxide levels, due to shunting of blood through the lungs, air trapping, or alveolar hypoventilation, further increase retinal perfusion. Systemic signs that accompany these changes include dyspnea, cyanosis, clubbing of fingers and toes, and the plethoric facies produced by secondary polycythemia. Obliteration of the pulmonary vascular bed in more advanced states results in increased pulmonary vascular resistance, which in turn may lead to pulmonary hypertension and right-sided heart failure. The clinical findings include increased venous pressure, peripheral edema, and hepatomegaly. As the inverting blood-gas ratios continue to worsen, headaches, tremors, twitching of the extremities, and alterations in consciousness ensue.2 Cerebral and retinal vascular resistance decline, giving way to progressive vasodilation and increased blood flow, which along with increased serum viscosity, secondary polycythemia, and increased venous pressure produce the full clinical picture of chronic pulmonary failure.
Because there is greater resistance in the arterial than venous walls, the veins tend to dilate more than arteries in response to the changes described earlier. The dilation tends to be segmental, as a result of the patchy fibrosis that replaces the normal elastic smooth muscle in the vessel walls of older patients. The result is pronounced irregularity of vessel caliber, which is especially evident at arteriovenous crossings, where the artery and vein share a common adventitial sheath. As pulmonary decompensation worsens, vascular configuration changes and hyperviscosity lead to occlusive and hemorrhagic events, producing retinal hemorrhages, macular edema, and optic disc edema.3 Visual acuity and visual fields may remain normal despite optic nerve swelling but may become severely compromised if macular hemorrhages and edema ensue. If the blood gas pattern can be normalized even at this stage, retinal and conjunctival vascular patterns may revert to normal.
CYSTIC FIBROSIS OF THE PANCREAS
Cystic fibrosis of the pancreas (fibrocystic disease of the pancreas, mucoviscoidosis) was first reported by Fanconi in Switzerland in 1936. In 1938, Anderson defined this entity as a separate and distinct disorder. Tsui localized the defective gene locus to the long arm of chromosome 7
in 1985 and with Collins was then able to clone the gene in 1989.4 Currently, there are 1,794 mutations listed in the CFTR (cystic fibrosis transmembrane conductance regulator) mutations database.5 Screening panels can identify up to 90% of the CFTR mutations, which aids in the ability to diagnose this disease at an early age.6 All 50 states as well as the District of Columbia now require newborn screening for cystic fibrosis.
in 1985 and with Collins was then able to clone the gene in 1989.4 Currently, there are 1,794 mutations listed in the CFTR (cystic fibrosis transmembrane conductance regulator) mutations database.5 Screening panels can identify up to 90% of the CFTR mutations, which aids in the ability to diagnose this disease at an early age.6 All 50 states as well as the District of Columbia now require newborn screening for cystic fibrosis.
The incidence of this disease is 1:3,500 live births, and it is estimated that approximately 30,000 individuals in America have cystic fibrosis.7, 8 It is most commonly found among whites, and it displays an autosomal recessive inheritance pattern. Cystic fibrosis is the most frequent lethal genetic disorder of white children. The inborn error of metabolism appears to involve a protein that acts as a membrane channel of chloride ions, preventing secretion of chloride and water into mucus by lung epithelial cells.
The disease is usually recognized in children and adolescents. It is the most common cause of chronic obstructive pulmonary disease and pancreatic insufficiency in the first three decades of life. The prognosis was once quite poor (80% died before age 20), but antibiotics and pulmonary physiotherapy have greatly lengthened life expectancy. The mean predicted survival age has recently been reported at 37.4 years of age; this value reflects the age at which half of the patients in the cystic fibrosis registry are expected to survive.7 Some adults with chronic pulmonary disease have proved to have previously undiagnosed cystic fibrosis.
Cystic fibrosis causes dysfunction of almost all exocrine, eccrine, and some endocrine glands. The resultant effect is an abnormal mucus secretion that causes obstruction of single mucin-producing cells. The pancreas secretes less enzyme (e.g., trypsin, lipase, and amylase), so malabsorption ensues with its attendant deficiency disorders. The islets of Langerhans are not directly affected, but their secondary ablation by exocrine gland cicatrization makes diabetes 25 times more common than in the general population. Ketoacidosis is rare because glucagon-producing cells are also destroyed by the fibrocystic changes. In the lungs, inspissated secretions cause blockage of the bronchioles with overinflation of alveolar spaces and secondary infection. Cirrhosis of the liver from biliary obstruction is present in 25% of autopsies. The abnormal eccrine glands lose excess sodium, potassium, and chloride in sweat and calcium and phosphorous in saliva.
Where there is a positive screening test or high enough clinical suspicion for the diagnosis of cystic fibrosis, the next step and gold standard in evaluation is a sweat chloride test. On the basis of the results, a clinical diagnosis can be made and may prompt additional testing of other family members. When the results are equivocal (30 to 59 mmol per L), further testing via DNA analysis can be done and the sweat test repeated in the months to follow.6 Absence or marked decrease of pancreatic enzymes (e.g., amylase, lipase, or trypsin) in aspirated duodenal contents, increased stool fat, chronic lung disease, and familial history may also be examined to aid the process of making the diagnosis.6 The identification of the cystic fibrosis gene locus now allows definitive, though controversial, prenatal and carrier diagnosis as well.9
Symptoms, for the most part, relate to pulmonary disease and to a lesser degree pancreatic insufficiency. Pancreatic insufficiency causes malabsorption with steatorrhea and malnutrition. Pulmonary problems present clinically as frequent recurrent infections (bronchopneumonia, bronchiectasis, lung abscess), which may lead to lobar atelectasis, pneumothorax, hemoptysis, and mediastinal and subcutaneous emphysema. In patients with severe or long-standing disease, cor pulmonale and pulmonary hypertension occur.
The typical clinical pattern is one of a chronically ill, malnourished child with steatorrhea and recurrent pulmonary infections. It is recommended that these children/adolescents be monitored closely each year with extensive clinical evaluation and testing. Patients with cystic fibrosis should have annual pulmonary function testing, yearly influenza vaccine, periodic respiratory culture, oral glucose tolerance testing, liver function evaluation, and vitamin level monitoring.7
Ocular signs and symptoms seem to correlate most closely with the severity and rapidity of the pulmonary insufficiency.10 The most significant factor appears to be retention of carbon dioxide (hypercapnia), although chronic ischemia and often diabetes mellitus play a significant part in retinal pathology. The most common findings are in the retina and include venous dilation, tortuosity, and retinal hemorrhages (posterior pole). Papilledema may occur, and intraretinal edema at the posterior pole is occasionally found, perhaps as a result of vascular incompetence.10 It may lead to a cystic macula or even a lamellar macular hole. Except for these later findings, the retinal changes are mostly reversible with improvement in the pulmonary status (Fig. 24.1).
Ocular surface changes are generally minimal, but abnormal tear function and a propensity for blepharitis have been demonstrated. Xerophthalmia and nyctalopia have occasionally been reported as sequelae to vitamin A deficiency.11, 12 There is also some evidence to support abnormal corneal endothelial function, especially when aggravated by hyperglycemia13 (Fig. 24.2).
Neuro-ophthalmic manifestations include retrobulbar neuritis and preganglionic oculosympathetic paresis.14 Optic nerve functional deficiencies manifested by decreased contrast sensitivity, abnormal visual evoked potentials, and
dyschromatopsia have been reported in association with antibiotic use (especially chloramphenicol).15, 16 and 17 Hypoxia and vitamin deficiencies may contribute as well.
dyschromatopsia have been reported in association with antibiotic use (especially chloramphenicol).15, 16 and 17 Hypoxia and vitamin deficiencies may contribute as well.
The current treatment remains directed toward preventing progressive pulmonary destruction through the use of antibiotics, including inhaled tobramycin and aztreonam, to target organisms, such as Pseudomonas aeruginosa, that colonize the respiratory tract.18 Pulmonary physiotherapy plays a vital role in the mobilization of secretions in order to prevent recurrent respiratory infections. Researchers are evaluating the possibility of utilizing inhaled hypertonic saline in infants to break up mucus secretion and maintain lung function.7 Bilateral lung transplantation is still being explored as a potential sustaining procedure for patients with preterminal disease.19 Genetic engineering offers promising new therapeutic approaches in the form of gene replacement targeting the CFTR mutation, as well as retrovirus-based medication that when inhaled may help to thin lung mucus.16, 18
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